The goal of this proposal is to develop conotoxins as topical local anesthetics for treatment of burn pain. Severe burn injuries often result in intense pain which is currently treated with opiates. Recently, a few studies have suggested that topical treatment with local anesthetics , which block sodium channels, may provide some pain relief. Conopeptide mu-O-MrVIB, a peptide neurotoxin isolated from marine snail Conus marmoreus, has been shown to be a very potent and selective neuronal sodium channel blocker. Our preliminary results indicate that synthetic MrVIB possesses a local anesthetic effect of long duration that may represent a novel therapy for severe burn pain. In phase I of the proposed research, we plan to optimize production of mu-O-MrVIB and to produce three additional homologous conopeptides isolated by Cognetix from different Conus species. We will evaluate the efficacy of these conopeptides by determining their in vivo potency, time of onset and duration of action in a rat skin flinch assay. In addition, we will determine their effects on cardiovascular and CNS systems. We also plan to initiate evaluation of selected mu-O- conopeptides in an animal model of bum injury. PROPOSED COMMERCIAL APPLICATIONS: Of the 2 million burn accidents each year in the U.S., 60,000 to 200,000 injuries are severe enough to require hospitalization. A product which relieved severe and persistent burn pain with greater efficacy and fewer side effects than opiates would be demanded by patients. We propose that mu-O-conopeptides represent a new class of long-acting local anesthetics which may serve this indication. Estimates are that worldwide sales of local anesthetics total about $500 million.